A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences

Hoffmann, Thomas J.; Eeden, Stephen K. Van Den; Sakoda, Lori C.; Jorgenson, Eric; Habel, Laurel A.; Graff, Rebecca E.; Passarelli, Michael N.; Cario, Clinton L.; Emami, Nima C.; Chao, Chun; Ghai, Nirupa R.; Shan, Jun; Ranatunga, Dilrini K.; Quesenberry, Charles P.; Aaronson, David S.; Presti, Joseph C.; Wang, Zhaoming; Berndt, Sonja I.; Chanock, Stephen J.; McDonnell, Shannon K.; French, Amy J.; Schaid, Daniel J.; Thibodeau, Stephen N.; Li, Qiyuan; Freedman, Matthew L.; Penney, Kathryn L.; Mucci, Lorelei A.; Haiman, Christopher A.; Henderson, Brian E.; Seminara, Daniela; Kvale, Mark N.; Kwok, Pui Yan; Schaefer, Catherine; Risch, Neil; Witte, John S.

doi:10.1158/2159-8290.cd-15-0315

Cited by 113 publications

(116 citation statements)

References 60 publications

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“…OCT3/ SLC22A3 is highly expressed in the prostate indicating that metformin uptake would not be an issue 284 . But interestingly, low SLC22A3 expression is a strong predictor of poor prognosis in prostate cancer patients 285–288 . Whether changes in SLC22A3 expression could in part explain some of the differences between the contrasting retrospective analyses of metformin’s effects on prostate cancer remains to be determined.…”

Section: Targeting Ampkmentioning

confidence: 99%

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A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer

Khan

Frigo

2017

Nat Rev Urol

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The 5′-AMP-activated protein kinase (AMPK) is a master regulator of cellular homeostasis. Despite AMPK’s known function in physiology, its role in pathological processes such as prostate cancer is enigmatic. However, emerging evidence is now beginning to decode AMPK’s paradoxical role in cancer and therefore inform clinicians if and how AMPK could be therapeutically targeted. Here, we propose that it is the spatiotemporal regulation of AMPK complexes that govern the kinase’s role in cancer. We hypothesize that different upstream stimuli will activate select subcellular AMPK complexes. This is supported by the distinct subcellular locations of the various AMPK subunits. Each of these unique AMPK complexes regulate discrete downstream processes that can be tumor suppressive or oncogenic. It is the weighted net function of these downstream signaling events, influenced by additional prostate-specific signaling, that determines AMPK’s final biological output.

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Section: Targeting Ampkmentioning

confidence: 99%

“…One would predict that tumors with low OCT3 levels would have decreased sensitivity to metformin. As risk allele variants associated with SLC22A3 expression are known 285,286,288,289 , these could be screened prior to selection of patients for future clinical trials.…”

Section: Targeting Ampkmentioning

confidence: 99%

A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer

Khan

Frigo

2017

Nat Rev Urol

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“…Mutations in GGCX are typically associated with combined deficiency of vitamin K-dependent clotting factors 1 and hemorrhagic disease [17]. Although there is no evidence this gene plays a role in bladder cancer, it has been associated with prostate cancer in several GWAS [18, 19]. It is possible that genetic variation in this gene is also a risk factor for bladder cancer, but that synergistic interactions between multiple SNPs are necessary to observe a phenotype.…”

Section: Resultsmentioning

confidence: 99%

Complex systems analysis of bladder cancer susceptibility reveals a role for decarboxylase activity in two genome-wide association studies

et al. 2016

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BackgroundBladder cancer is common disease with a complex etiology that is likely due to many different genetic and environmental factors. The goal of this study was to embrace this complexity using a bioinformatics analysis pipeline designed to use machine learning to measure synergistic interactions between single nucleotide polymorphisms (SNPs) in two genome-wide association studies (GWAS) and then to assess their enrichment within functional groups defined by Gene Ontology. The significance of the results was evaluated using permutation testing and those results that replicated between the two GWAS data sets were reported.ResultsIn the first step of our bioinformatics pipeline, we estimated the pairwise synergistic effects of SNPs on bladder cancer risk in both GWAS data sets using Multifactor Dimensionality Reduction (MDR) machine learning method that is designed specifically for this purpose. Statistical significance was assessed using a 1000-fold permutation test. Each single SNP was assigned a p-value based on its strongest pairwise association. Each SNP was then mapped to one or more genes using a window of 500 kb upstream and downstream from each gene boundary. This window was chosen to capture as many regulatory variants as possible. Using Exploratory Visual Analysis (EVA), we then carried out a gene set enrichment analysis at the gene level to identify those genes with an overabundance of significant SNPs relative to the size of their mapped regions. Each gene was assigned to a biological functional group defined by Gene Ontology (GO). We next used EVA to evaluate the overabundance of significant genes in biological functional groups. Our study yielded one GO category, carboxy-lysase activity (GO:0016831), that was significant in analyses from both GWAS data sets. Interestingly, only the gamma-glutamyl carboxylase (GGCX) gene from this GO group was significant in both the detection and replication data, highlighting the complexity of the pathway-level effects on risk. The GGCX gene is expressed in the bladder, but has not been previously associated with bladder cancer in univariate GWAS. However, there is some experimental evidence that carboxy-lysase activity might play a role in cancer and that genes in this pathway should be explored as drug targets. This study provides a genetic basis for that observation.ConclusionsOur machine learning analysis of genetic associations in two GWAS for bladder cancer identified numerous associations with pairs of SNPs. Gene set enrichment analysis found aggregation of risk-associated SNPs in genes and significant genes in GO functional groups. This study supports a role for decarboxylase protein complexes in bladder cancer susceptibility. Previous research has implicated decarboxylases in bladder cancer etiology; however, the genes that we found to be significant in the detection and replication data are not known to have direct influence on bladder cancer, suggesting some novel hypotheses. This study highlights the need for a complex systems approach to the geneti...

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“…Numerous reports suggest significant differences between prostate cancers in Caucasians and men of other ethnicities. [110-112] With few exceptions,[55] all the commercially available tests were discovered and validated in a fairly homogenous Caucasian patient population, and studies are needed to determine the applicability of these assays in other demographics. This is particularly important in African American (AA) men who experience a higher incidence and mortality due to prostate cancer.…”

Section: Other Considerations Of Tissue-based Biomarkersmentioning

confidence: 99%

Tissue-based biomarkers in prostate cancer

Clinton

Bagrodia²,

Lotan³

et al. 2017

Expert Review of Precision Medicine and Drug Development

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Introduction Prostate cancer is a heterogeneous disease. Existing risk stratification tools based on standard clinlicopathologic variables (prostate specific antigen [PSA], Gleason score, and tumor stage) provide a modest degree of predictive ability. Advances in high-throughput sequencing has led to the development of several novel tissue-based biomarkers that can improve prognostication in prostate cancer management. Areas Covered The authors review commercially-available, tissue-based biomarker assays that improve upon existing risk-stratification tools in several areas of prostate cancer management, including the appropriateness of active surveillance and aiding in decision making regarding the use of adjuvant therapy. Additionally, some of the obstacles to the widespread adoption of these biomarkers and discuss several investigational sources of new biomarkers are discussed. Expert Commentary Work is ongoing to answer pertinent clinical questions in prostate cancer management including which patients should undergo biopsy, active surveillance, receive adjuvant therapy, and what systemic therapy is best in the first-line. Incorporation into novel biomarkers may allow for the incorporation of a ‘personalized’ approach to management. Further validation will be required and questions of cost must be considered before wide scale adoption of these biomarkers. Tumor heterogeneity may impose a ceiling on the prognostic ability of biomarkers using currently available techniques.

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A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences

Cited by 113 publications

References 60 publications

A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer

A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer

Complex systems analysis of bladder cancer susceptibility reveals a role for decarboxylase activity in two genome-wide association studies

Tissue-based biomarkers in prostate cancer

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